<p>Mango leaves serve as crucial energy centers for tree growth and have high economic, nutritional, and medicinal value. Cuticular wax provides the primary defense against external environmental stresses and is essential for healthy leaf development. However, the molecular mechanisms underlying cuticular wax synthesis in mango leaves remain largely unexplored. Accordingly, this study investigated the mechanisms of leaf cuticular wax synthesis in four mango varieties— ‘Yiwen’, ‘Kent’, ‘Chin Hwang’, and ‘Red Ivory’—<i>via</i> integrated metabolomics and transcriptomics approaches. Total wax content varied substantially among these varieties (25.99–119.28&#xa0;μg/cm²). A total of 93 distinct wax compounds were identified and categorized into eight classes, in which terpenoids, esters, and alkanes were the predominant ones. Cuticular wax synthesis was associated with 34 genes, including 18 key genes involved in the biosynthesis of very-long-chain fatty acids (VLCFAs) and their derivatives and 16 involved in terpenoid biosynthesis. Quantitative reverse transcription-polymerase chain reaction analysis revealed that the expression trends of 17 genes were largely consistent with those of the transcriptome. Based on these findings, we propose a biochemical pathway by which cuticular wax is synthesized in mango leaves. This study provides a robust theoretical framework for elucidating the mechanism of cuticular wax biosynthesis and offers valuable insights into improving tree health and increasing the economic value of mango leaves.</p>